Readout of histone methylation by Trim24 locally restricts chromatin opening by p53

Isbel, Luke; Iskar, Murat; Durdu, Sevi; Grand, Ralph S.; Weiss, Joscha; Hietter-Pfeiffer, Eric; Kozicka, Zuzanna; Michael, Alicia; Burger, Lukas; Thomä, Nicolas H.; Schübeler, Dirk

doi:10.1101/2022.08.23.504916

Cited by 4 publications

(4 citation statements)

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“…Numerous studies have assessed the impact of p53 on senescence and longevity 34–36 and recent studies highlight that restricted opening of the chromatin by p53 is fundamental for cellular transcriptional programs. 37 In nonvascular cells, the p53 protein mainly localizes to the cytoplasm and its rapid ubiquitination and turnover maintains a low level of expression. 38 In response to prolonged cellular stress, the p53 protein is stabilized as a result of increased expression of the main p53 E3 ubiquitin ligase, MDM2.…”

Section: Discussionmentioning

confidence: 99%

Disrupted Binding of Cystathionine γ-Lyase to p53 Promotes Endothelial Senescence

Hu,

Leisegang,

Looso

et al. 2023

Circulation Research

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Background: Advanced age is unequivocally linked to the development of cardiovascular disease; however, the mechanisms resulting in reduced endothelial cell regeneration remain poorly understood. Here, we investigated novel mechanisms involved in endothelial cell senescence that impact endothelial cell transcription and vascular repair after injury. Methods: Native endothelial cells were isolated from young (20±3.4 years) and aged (80±2.3 years) individuals and subjected to molecular analyses to assess global transcriptional and metabolic changes. in vitro studies were conducted using primary human and murine endothelial cells. A murine aortic reendothelialization model was used to examine endothelial cell regenerative capacity in vivo. Results: RNA sequencing of native endothelial cells revealed that aging resulted in p53-mediated reprogramming to express senescence-associated genes and suppress glycolysis. Reduced glucose uptake and ATP contributed to attenuated assembly of the telomerase complex, which was required for endothelial cell proliferation. Enhanced p53 activity in aging was linked to its acetylation on K120 due to enhanced activity of the acetyltransferase MOZ (monocytic leukemic zinc finger). Mechanistically, p53 acetylation and translocation were, at least partially, attributed to the loss of the vasoprotective enzyme, CSE (cystathionine γ-lyase). CSE physically anchored p53 in the cytosol to prevent its nuclear translocation and in its absence inhibited Akt-mediated MOZ phosphorylation, which in turn increased MOZ activity and subsequently p53 acetylation. In mice, the endothelial cell–specific deletion of CSE activated p53, induced premature endothelial senescence, and arrested vascular repair after injury. In contrast, the adeno-associated virus 9–mediated reexpression of an active CSE mutant retained p53 in the cytosol, maintained endothelial glucose metabolism and proliferation, and prevented endothelial cell senescence. Adenoviral overexpression of CSE in native endothelial cells from aged individuals maintained low p53 activity and reactivated telomerase to revert endothelial cell senescence. Conclusions: Aging-associated impairment of vascular repair is partly determined by the vasoprotective enzyme CSE.

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Section: Discussionmentioning

confidence: 99%

Disrupted Binding of Cystathionine γ-Lyase to p53 Promotes Endothelial Senescence

Hu,

Leisegang,

Looso

et al. 2023

Circulation Research

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“…Proteins with a paired domain, such as Trim24, which contains a PHD and a Bromo domain targeting unmodified H3K4 and acetylated H3K23, respectively, has been shown to bind a single histone tail bearing these two marks in vitro (Tsai et al 2010). However recent work indicates that H3K23ac is absent from Trim24-binding sites in mESCs and does not appear to play a role in Trim24 localization in vivo (Isbel et al 2023).…”

Section: Discussionmentioning

confidence: 99%

A dual histone code specifies the binding of heterochromatin protein Rhino to a subset of piRNA source loci

Akkouche,

Kneuss,

Bornelöv

et al. 2024

Preprint

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Animal germ cells deploy a specialized small RNA-based silencing system, called the PIWI-interacting RNA (piRNA) pathway, to prevent unwanted expression of transposable elements and maintain genome integrity. In Drosophila germ cells, the majority of piRNA populations originate from dual-strand piRNA clusters, genomic regions highly enriched in transposon fragments, via an elaborate protein machinery centred on the heterochromatin protein 1 homolog, Rhino. Although Rhino binds to peptides carrying trimethylated H3K9 in vitro, it is not fully understood why in vivo only a fraction of H3K9me3-decorated heterochromatin is occupied by Rhino. Recent work uncovered that Rhino is recruited to a subset of piRNA clusters by the zinc finger protein Kipferl. Here we identify a Kipferl-independent mode of Rhino targeting that is dependent on the histone H3 lysine 27 methyltransferase Enhancer of Zeste and the presence of H3K9me3 and H3K27me3 marks. At Kipferl-independent sites, we find that Rhino, through its dimeric chromodomain, specifically binds to loci marked by both H3K9me3 and H3K27me3. These results expand our understanding of the characteristic binding profile of the heterochromatin protein Rhino. Our work reveals a role for dual histone modifications in defining the binding specificity of a chromatin protein.

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“…Protein digestion was carried out as previously described 48 . In brief, beads were resuspended in 5 μl digestion buffer (3 M guanidinium hydrochloride, 20 mM EPPS (Hepps; pH 8.5), 10 mM chloroacetamide and 5 mM tris(2-carboxyethyl)phosphine) and digested with 1 μl of 0.2 μg μl −1 Lys-C at room temperature for 4 h. In total, 17 μl (50 mM) HEPES (pH 8.5) were added to the beads, followed by the addition of 1 μl (0.2 μg μl −1 ) trypsin.…”

Section: Co-ip Followed By Mass Spectrometrymentioning

confidence: 99%

“…Co-IP MS enrichment analysis was carried out as previously described 48 . In brief, protein identification and relative quantification were performed with MaxQuant (v.1.5.3.8) using Andromeda as the search engine 50 and label-free quantification 51,52 .…”

Section: Co-ip Ms Protein Enrichment Analysismentioning

confidence: 99%

Systematic assessment of ISWI subunits shows that NURF creates local accessibility for CTCF

Iurlaro,

Masoni,

Flyamer

et al. 2024

Nat Genet

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Catalytic activity of the imitation switch (ISWI) family of remodelers is critical for nucleosomal organization and DNA binding of certain transcription factors, including the insulator protein CTCF. Here we define the contribution of individual subcomplexes by deriving a panel of isogenic mouse stem cell lines, each lacking one of six ISWI accessory subunits. Individual deletions of subunits of either CERF, RSF, ACF, WICH or NoRC subcomplexes only moderately affect the chromatin landscape, while removal of the NURF-specific subunit BPTF leads to a strong reduction in chromatin accessibility and SNF2H ATPase localization around CTCF sites. This affects adjacent nucleosome occupancy and CTCF binding. At a group of sites with reduced chromatin accessibility, CTCF binding persists but cohesin occupancy is reduced, resulting in decreased insulation. These results suggest that CTCF binding can be separated from its function as an insulator in nuclear organization and identify a specific role for NURF in mediating SNF2H localization and chromatin opening at bound CTCF sites.

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Readout of histone methylation by Trim24 locally restricts chromatin opening by p53

Cited by 4 publications

References 128 publications

Disrupted Binding of Cystathionine γ-Lyase to p53 Promotes Endothelial Senescence

Disrupted Binding of Cystathionine γ-Lyase to p53 Promotes Endothelial Senescence

A dual histone code specifies the binding of heterochromatin protein Rhino to a subset of piRNA source loci

Systematic assessment of ISWI subunits shows that NURF creates local accessibility for CTCF

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